Female gender is a risk factor for the development of Alzheimer's disease (AD). Accumulating evidence suggests that the large reduction in estrogen levels that occurs in postmenopausal women is a primary variable underlying this risk factor. Importantly, the clinical use of estrogen replacement therapy has been demonstrated to both delay the onset of AD and slow its progression. Currently, it is unclear which of estrogen's many cellular effects contribute to its inhibition of AD pathology. In this grant application, we propose a novel neuroprotective mechanism of estrogen and predict that it functions to increase neuronal resilience against degenerative stimuli implicated in AD neurodegeneration. Based upon recent advances in the fields of endocrinology and oncology, we theorize that in estrogen- responsive brain regions (e.g., hippocampus, entorhinal cortex, amygdala) estrogen modulates the expression of apoptosis-related proteins, perhaps via a classic estrogen receptor-dependent genomic pathway. In particular, our preliminary data suggest that estrogen significantly increases expression of the anti-apoptotic protein Bcl-xL. As a consequence of its regulation of apoptosis-related proteins, we theorize that estrogen sways the balance of neuronal apoptotic pathways towards enhanced viability, thereby increasing the resistance of estrogen-responsive neurons to degeneration. Thus, the loss of estrogen following menopause is predicted to decrease levels of an important endogenous modulator of neuronal viability, rendering estrogen-responsive brain regions vulnerable to apoptotic challenge. We propose three aims to investigate this theory: (1) Using cell culture and in vivo paradigms, we will evaluate estrogen's ability to regulate neuronal expression of apoptosis-related proteins. We will identify estrogen target proteins, characterize estrogen effects on target proteins, and determine the role of receptor activation and differential receptor subtype in these estrogen actions; (2) We will investigate our prediction that functional consequences of estrogen's regulatory actions include decreased activation of specific apoptotic pathways (e.g., caspase-mediated proteolysis) and increased neuronal viability using both in vitro and in vivo models; (3) We will extend findings made in experimental systems (Aims 1, 2) to the human condition by evaluating the estrogen/apoptosis relationship in brain tissue from cases that vary by gender, AD pathology, and hormonal status. We anticipate that our proposed studies will generate new insight into the ability of estrogen to modulate neuronal viability throughout life, from neural development through age-related neurodegenerative disorders.